Hematopoietic cell transplantation (HCT) has curative potential for individuals with sickle cell disease. While the results of conventional HCT have been good, this treatment carries risks of significant short-term and long-term toxicities. These toxicities are particularly pronounced among adults with sickle cell disease. For this reason, HCT has been reserved for children who have experienced severe symptoms that predict a poor outcome. Of interest, some patients developed stable donor-host hematopoietic chimerism after conventional HCT. Due to a natural enrichment of donor erythrocytes in the blood, those who developed stable chimerism had a significant clinical benefit, even when there was a minority of donor cells. These observations have paralleled efforts to develop less-toxic, non-myeloablative preparative regiments for transplantation, proved first in a canine model of transplantation, and subsequently translated successfully in clinical trials for older adults with hematological malignancies. Thus, this proposal, based on these supporting pre-clinical and clinical investigations, aims to investigate a modified transplant procedure for young adults with sickle cell disease that significantly reduces the toxicity of HCT, yet retains its therapeutic benefit. This is a novel approach, conducted in the outpatient setting, which will rely upon the ability to establish and maintain donor-host chimerism. It will be achieved by combining less toxic, non-myeloablative pre-transplant therapy with modulated postgrafting immunosuppression aimed at controlling host-versus-graft and graft-versus-host reactions. This investigation will employ a network of collaborative sickle cell and transplant centers to identify and enroll eligible patients. The primary endpoint of stable donor cell engraftment will be determined and secondary endpoints to measure the impact on sickle cell-related symptoms and end-organ damage will be followed. If successful, this novel approach will expand the availability of HCT for older individuals with clinically significant hemoglobinopathies.